Opiates acting within the brainstem and spinal cord exert a potent modulatory influence over sensory processing which presumably mimicks the physiological functioning of an endogenous system characterized by the opioid peptides (enkephalins). Data suggest that cord opioid neurons act presynaptically on sensory afferents while in the brainstem the opioid interneuron is part of a circuit activating a descending serotonin (5-HT) and norepinephrine (NE) system. We will in the present work study factors which control the activation of this intrinsic enkephalin-monoamine circuit by measuring with high performance liquid chromatography and radioimmunoassay, their release in vivo from brainstem and spinal cord using local perfusions of the mesencephalic aqueduct (adjacent to the periaqueductal gray--a potent locus of opiate action) and a novel spinal perfusion procedure developed in this laboratory for the local superfusion of the rat and cat spinal cord in vivo. These experiments will first provide basic data regarding the physiological connectivity of the intrinsic system which is associated with endogenous opioid peptides. Secondly, our ability to measure reliably these materials (in the case of the monoamines, their metabolites) will permit us to examine in vivo in a relatively simple CNS system--the spinal cord--the essential question of whether these materials meet one of the primary criteria for a neurotransmitter, e.g. they are released in consequence to neural activity. Thirdly, our understanding of the pharmacology of the spinal modulatory systems will provide a rationale for future development in the control of pain.